Field of the Invention
The present invention relates to the field of cancer diagnostics and therapy, especially with respect to glucose metabolism and oncogenesis.
Related Art
Presented below is background information on certain aspects of the present invention as they may relate to technical features referred to in the detailed description, but not necessarily described in detail. That is, individual parts or methods used in the present invention may be described in greater detail in the materials discussed below, which materials may provide further guidance to those skilled in the art for making or using certain aspects of the present invention as claimed. The discussion below should not be construed as an admission as to the relevance of the information to any claims herein or the prior art effect of the material described.
The glucose intermediary metabolism often has been referred to as a “housekeeping” function (Bissell, 1981), but the increase in aerobic glycolysis in cancer, referred to as the “Warburg effect”, is creating much excitement again. The original hypothesis by Warburg stated that irreversible mitochondrial dysfunction is the underlying reason of the metabolic shift to aerobic glycolysis (Warburg, 1956). However, mitochondrial dysfunction is not always observed in cancer cells even when there is increased aerobic glycolysis (Bissell et al., 1976; Frezza and Gottlieb, 2009). The current literature views the metabolic alterations as a result of the pleiotropic response to oncogenic signaling, thus placing those pathways upstream of glycolytic metabolism (reviewed in: Kroemer and Pouyssegur, 2008; Levine and Puzio-Kuter, 2010; Vander Heiden et al., 2009). The most highly mentioned roles of increased glucose metabolism in cancer are contributions to the tumor's proliferation and survival. The glycolytic pathway is able to provide ATP independently of oxygen even when tumors confront a hypoxic microenvironment (Gatenby and Gillies, 2004). It is true that many intermediary glucose metabolites are utilized for diverse biosynthetic processes such as nucleotide and lipid syntheses (Vander Heiden et al., 2009). Also NADPH, a reducing equivalent generated by glucose metabolism, sequesters ROS and thus confers resistance to cell death (Bensaad et al., 2006; Vaughn and Deshmukh, 2008).
On the other hand, the idea that glucose levels trigger intra- and inter-cellular signaling has been accepted widely in the fields of diabetes and endocrinology. Glucose signaling has been shown to be linked to physiological and pathological events such as regulation of hormone secretion and “insulin resistance” (Marshall, 2006; Marty et al., 2007; Schuit et al., 2001). Intriguingly, Warburg theorized that the metabolic shift to glycolysis is “the origin of cancer cells” (Warburg, 1956). However, the demonstration of causative effects of the increased glucose metabolism itself on oncogenesis has eluded the field (see McKnight, 2010).
There is now broad recognition of the universality of increased aerobic glycolysis in cancer. Given the demonstration of the impact of the microenvironment, including the composition of the medium (Bissell, 1981), on gene expression and integration of signaling events observed in 3D organotypic assays in laminin-rich extracellular matrix gels (lrECM; summarized in Bissell et al., 2005), we hypothesized that glucose uptake and metabolism would be an integral component of the tissue integration plan. We reasoned that if uptake and metabolism of glucose were hyper-activated, by mutation or increased levels of glucose in tissues and/or media, other oncogenic pathways could be activated reciprocally. Here we directly address this important but neglected possibility in cancer promotion using 3D lrECM cultures where both malignant and nonmalignant breast cells behave phenotypically as if they were in vivo (Petersen et al., 1992).
Described below are methods utilizing the present findings that inhibition of glucose uptake or metabolism suppresses the known oncogenic pathways and results in “phenotypic reversion” in a number of breast cancer cells. Significantly, forced increase in glucose uptake (and thus metabolism) in the examples below activated some of the other signaling pathways involved in oncogenesis, leading to a disorganized and malignant-like phenotype in non-malignant breast cells. We show that both the glycolytic pathway and the hexosamine biosynthetic pathway (HBP) are involved in the reciprocal regulation. Our findings suggest strongly that increased glucose uptake and metabolism in non-malignant cells compared to normal unstressed cells could be an oncogenic event analogous to activation of EGFR, β1 integrin, PI3K-Akt or MEK-ERK. We also unravel mechanisms of the intricate and hitherto unknown reciprocal activation by which glucose metabolism directly integrates with the other signaling pathways in 3D.